Catechol-O-methyltransferase: substrate-specificity and stereoselectivity for β-adrenoceptor agents

Abstract

1. Isoprenaline, isoetharine, rimiterol, dobutamine and nadolol were investigated as substrates for purified pig-liver catechol-O-methyltransferase using a sensitive spectro-photometric assay. Kinetic parameters, K_m and V_max, were defined and the apparent first-order rate constant (V_max/K_m) was derived.

2. On the basis of the apparent first-order rate constant, rimiterol was found to be a 1.5-fold and dobutamine a 5-fold better substrate for catechol-O-methyltransferase than isoprenaline; isoetharine shows no improvement over isoprenaline.

3. Nadolol is not a substrate for catechol-O-methyltransferase.

4. O-Methylation of isoprenaline- and noradrenaline-enantiomers was found to be stereoselective: catechol-O-methyltransferase shows selectivity towards the laevo (-) isomer with respect to the (+) form or racemic mixture.

5. The investigation indicated stereochemical and steric determinants important in the interaction of catechol-O-methyltransferase with physiologically and clinically important β-adrenoceptor agents.